1. Drugs and Treatments for Ataxia Christopher M. Gomez The University of Chicago

2. Two types of treatments Disease-modifying (neuroprotective) Symptomatic

3. Disease-modifying Very few options right now. Most will be highly disease specific Some exceptions – AVED, or other disorders of vitamin E deficiency – Hypothyroidism – Immune mediated ataxias Disorders with some promise – Friedreichs ataxia: anti-oxidants, e.g. CoQ10, vitamin E, HDAC inhib. – Immunological disorders, esp MS: immunotherapies Many promising avenues and drugs under consideration – e.g. anti-oxidants, kinase inhibitors, protease inhibitors, stem cells

4. Symptomatic treatments Target to individual symptoms. Gold standard examples are: – L-dopa for Parkinson’s – Seizure medicines for epilepsy May not be disease-specific. Concept of negative vs positive symptoms All drugs have some side effects

5. Symptoms Ataxia (motor incoordination, gait, limbs, speech) Ataxic episodes Tremor – Action – Resting Vertigo Blurred vision Spasticity Rigidity, slowness of movements Fatigue

6. Ataxia Ataxia (motor incoordination, gait, limbs, speech) – Amantadine (Symmetrel) – Buspirone (Buspar) Ataxic episodes – Acetazolamide (Diamox) – Topiramide (Topamax) – Valproate (Depakote)

7. Tremor Resting – L-dopa (Sinemet) Intention/Action – Propranolol (Inderal) – Primidone (Mysoline) – Clonazepam (Klonopin) – Levitiracetam (Keppra) – Carbemazemine (Tegretol) – Isonoazid (INH)

8. Vertigo and Blurred vision Meclizine (Antivert) Acetazolamide (Diamox) Topiramate (Topamax) Gabapentin (Neurontin) Baclofen (Lioresal) 3, 4 Diaminopyridine Ondansetron (Zofran) Valproate (Depakote)

9. Non-ataxia motor symptoms Spasticity – Baclofen (Lioresal) – Tizanidine (Xanaflex) Dystonia – Baclofen (Lioresal) – Botulinum (Botox) Rigidity, slowness of movements – Amantadine (Symmetrel) – L-dopa (Sinemet)

10. Sleep disorders Restless legs – L-dopa (Sinemet) – Pramipexole (Mirapex) Sleep apnea – C-PAP REM behavior disorder – Clonazepam (Klonopin)

11. Novel Concept: Potential for Deep brain stimulation (DBS) in the treatment of tremor in ataxia

12. Deep Brain Stimulation

13. DBS history different targets in brain Ventral intermediate nucleus (VIM) DBS for ET and medically refractory parkinsonian tremor in 1997 Globus pallidus interna (GPi) and subthalamic nucleus (STN) DBS for PD in 2002 GPi and STN DBS for primary dystonia under humanitarian device exemption program in 2003 Caudal Zona Incerta (cZi) tremors, dystonia in PD and MS

14. DBS Anatomy zona incerta

15. Anatomic Location and Connection of cZi Plaha et al 2006, Brain 129: 1732-1747

16. Target Sites for DBS Therapy Vim Thalamus: Essential Tremor Subthalamic Nucleus: Parkinson’s disease and Dystonia Globus Pallidus: Parkinson’s disease and Dystonia cZI

17. Zona incerta (cZi) Very effective in controlling various tremors, PD and dystonia –Better than VIM in controlling various tremors by electrode-by-electrode comparison, including intention tremor and proximal tremor. –Better than STN in controlling PD symptoms in direct comparison. –Very effective in controlling various dystonia as well –Possibly less complications than VIM based on current knowledge

18. DBS Stereotactic Frame: used for image guided target localization

19. DBS for MS tremor OFFON

20. DBS for MS tremor OFFON

21. DBS for MS tremor OFFON

22. Novel concept cZi DBS might be a good target to control various symptoms of SCA, particularly debilitating tremors, with a better efficacy and few complications. A successful case of cZi DBS on SCA2 was reported in the literature (Freund et al, 2007).

23. Inclusion criteria with SCA for cZi DBS SCAx Severe symptoms affecting daily functions Failed Propranolol at 320mg/d Failed Primidone (Mysoline) at 250mg/d. Optional: Failed either Keppra, Sinemet, or Xyrem (if symptoms respond to alcohol) No significant depression or dementia Generally healthy Realistic expectation Good family support

25. Surgery and Measurements DBS Surgery – We place DBS electrodes along the VIM to cZi area, with upper 2 electrodes in VIM and bottom 2 electrodes in cZi area. Measurements of cZi vs VIM DBS – Fahn-Tolossa-Marin Tremor Rating Scale will be used for the quantitative comparison of the therapeutic outcomes. – UPDRS, ataxia and dystonia scales – Quality of life and mood scales.

26. Anatomic Location and Connection of cZi Plaha et al 2006, Brain 129: 1732-1747

27. Deep Brain Stimulation

28. Zona Incerta Gross Anatomy

29. Physiologic Target confirmation: Microelectrode Recording STN Border/SN 10sec 80ms Sagittal Section Through the Thalamus Border

30. Implantation of Unilateral DBS into the zona incerta, to be connected to a programmable IPG

31. Demographic and Clinical Characteristics: 4 Case Studies

32. Tremor Assessment Activities of Daily Living (ADL) Questionnaire: Scores 25 activities in terms of severity ranging from 1 to 4; high disability = 100 1 = able to do without difficulty 4 = cannot do without assistance

33. Tremor Assessment: Global Rating Score Patient and examiner independently rated the patient’s pre-op vs post-op status Score ranges from -3 (markedly worse) to +3 (markedly improved) No change (score = 0)

34. ADLs pre and post DBS MS

35. Tremor Global Rating Score PatientPhysicianAssessor:

36. SCA Very debilitating neurodegenerative disease with ataxia, various tremors, dystonia and parkinsonism. Balance and gait difficulty, dysarthria, clumsy of the hands. No effective medications so far.

37. Current targets for DBS are not effective for ataxia. Current VIM target is not very effective for intention tremor and proximal tremor, commonly seen in SCA VIM DBS is also associated with tolerance, dysarthria, and disturbance of gait and balance, particularly in bilateral procedures